20,21-acetonides of pregnenes, 16{62 -alkyl-17{60 ,20,21-trihydroxy pregnenes, and process for the production thereof

ABSTRACT

This invention relates to novel 20,21-acetonides of pregnenes and novel 16 Beta -alkyl-17 Alpha ,20,21-trihydroxy pregnenes, and processes for the production thereof. The compounds of this invention are useful intermediates; they provide an improved means for obtaining valuable 9 Alpha -fluoro-16 Beta alkylprednisolones and their 21-acylates which are known and highly active anti-inflammatory agents, for example, 9 Alpha fluoro-16 Beta -methylprednisolone (Betamethasone).

United States Patent [1 1 [111 3,725,392 Beal et al. 1 Apr. 3, 1973 [54] 20,21-ACETONIDES OF PREGNENES, [56] References Cited 16B-ALKYL-17a,20,2l-TRIHYDROXY PREGNENES, AND PROCESS FOR THE UNITED STATES PATENTS PRODUCTION THEREOF 3,182,056 5/1965 Tanabe ..260/239.55

[75] Inventors: Philip F. Beal, Kalamazoo; Kenneth Primary Examiner-Elbert L. Roberts Pmtage bmh 7 Attorney-John Kekich and Ward F. Nixon [73] Assignee: The Upjohn Company, Kalamazoo,

Mich- 57 ABSTRACT Filed; P 1971 This invention relates to novel 20,-2l-acetonides of [21] APPLNOJ 137051 pregnenes and novel 16B-alkyl-17a,20,2l-trihydroxy pregnenes, and processes for the production thereof. M m The compounds of this invention are useful inter- 52 US. Cl ..260/239.55 D, 260/2395 fnetiihtesifiivfiiivid'animisibva'meanfi 555m- 260I239-55 260/397-45 ing valuable 9a-fluoro-l6B-alkylprednisolones and their 2l-acylates which are known and highly active [51] Illl. Cl ..V....L( :Q7C anti inflammatory agents for example 9 1 [58] Field of Search ..260/239.55 D, 397.45,

Machine Searched Steroids methylprdnisol one (Betarnethasone).

I 18 Claims, No Drawings 20,2l-ACETONIDES OF PREGNENES, l6B-ALKYL- l7a,20,2 l-TRIHYDROXY PREGNENES, AND PROCESS FOR THE PRODUCTION THEREOF DETAILED nEsiurTioN OF THE INVENTION The novel intermediate; of tfis invention and processes for the production thereof are illustratively represented by the following sequence of formulas:

l HzC-O /R1 HzCO R I i HC O Rz H 0 Rz U YY 2 2 0 g V VI l to VII 3-enol others \3-enarnines valeric,

'whimiis'ac'yl; R and R taken separately are each hydrogen, alkyl, aralkyl, or aryl; R, and R taken together with the attached carbon represent cycloalkyl; X is alkoxy or the radical,

in which R and R taken separately are each alkyl and R and R taken together with constitute a sai'urrd'heifiiciicammo radical; and the l,2-carbon atom linkage is a single bond linkage or a double bond linkage.

In this application the wavy line appearing at the 20- position represents the 0: (alpha) configuration, the [3 (beta) configuration or mixtures thereof.

The term acyl means the acyl radical of an organic carboxylic acid preferably a hydrocarboncarboxylic acid, of one to -18 carbon atoms, inclusive, such as acetic, propionic, butyric, isobutyric, tert.-butylacetic, isovaleric, caproic, caprylic, decanoic, dodecanoic, acrylic, crotonic, hexynoic, heptynoic, octynoic, cyclobutanecarboxylic, cyclopentanecarboxylic, cyclopentenecarboxylic, cyclohexanecarboxylic, dimethylcyclohexanecarboxylic, benzoic, toluic, naphthoic, ethylbenzoic, phenylacetic, naphthaleneacetic, phenylvaleric, cinnamic, phenylpropiolic, phenylpropionic, p-butoxyphenylpropionic, succinic, glutaric, dimethylglutaric, maleic, cyclopentylpropionic, myristic, palmitic, stearic acids, and the like.

The term alkyl means an alkyl radical of one to eight carbon atoms, inclusive, such as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, and isomeric forms thereof.

The term aralkyl means an aralkyl radical of seven 13 carbon atoms, inclusive, such as benzyl, phenethyl, phenylpropyl, benzhydryl, and the like.

The term aryl means an aryl radical of six to 12 carbon atoms, inclusive, such as phenyl, tolyl, xylyl, naphthyl, diphenyl, halophenyl, nitrophenyl, and the like.

The term cycloalkyl means a cycloalkyl radical of three to eight carbon atoms, inclusive, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term alkoxy means an alkoxy radical of one 'to 12 carbon atoms, inclusive, such as methoxy, ethoxy,

propoxy, butoxy, pentoxy, hexyloxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, dodecoxy, and isomeric forms thereof.

The term cyclic amino radical" means asaturated 5 to 9 ring atom cyclic amino radical and is inclusive of pyrrolidino, alkylpyrrolidino, 2,2-dimethylpyrrolidino, and the like, piperidino, alkylpiperidino such as 2- methylpiperidino, 3-methylpiperidino, 4,4-dimethylpiperidino and the like, 4-methylpiperazino and the like, morpholino, alkylmorpholino, such as 2-methylmorpholino, 3-methylmorpholino and the like, hexamethyleneimino, homomorpholino, homopiperidino, thiomorpholino, octamethyleneimino, and the like.

The novel intermediates of the invention are prepared by subjecting a compound of formula 1 to a photosensitized oxygenation with a source of oxygen, for example, using a photosensitizer such as hematoporphyrin and a source of ultraviolet light in accordance with the procedures disclosed by Schneider et al., U. S. Pat. No. 3,281,415 to obtain the corresponding -hydroperoxides of formula 11. The com pounds of formula ll, thus obtained are then subjected to reduction with a tri-lower alkyl phosphite such as trimethylphosphite in accordance with the procedure disclosed by Gardner, U. S. Pat. No. 3,356,696, to obtain the corresponding 20aand ZOB-hydroxy compounds of formula Ill. The compounds of formula III are prepared directly from the starting materials I by a one pot" process or by reduction of the isolated hydroperoxy intermediates 11.

The compounds of formula III are then converted to the corresponding 17,20-acetonides of formula IV by reacting the selected 20-hydroxy compound with the appropriate aldehyde or ketone having the formula wherein R and R are as hereinbefore defined. The reaction is preferably conducted in the presence of an acid catalyst such as perchloric acid, p-toluenesulfonic acid, hydrochloric acid, and the like. Where the aldehyde or ketone is a liquid, it is convenient to employ an excess of same to serve as solvent for the reaction. Where the aldehyde or ketone is a solid, it is desirable to employ an inert organic solvent, such as tetrahydrofuran, dioxane, ether and the like, to facilitate the reaction. The compounds of formula IV, thus obtained, are then epoxidizcd by methods known in the art to obtain the corresponding l6a,17a-oxido compounds of formula V, for example, the selected compound 1V is dissolved in an appropriate solvent such as methylene chloride and treated with a peracid such as peracetic, perbenzoic or m-chloroperbenzoic acid to obtain the corresponding 1604,1701 -oxido compound, V. The compounds of formula V are then converted to the corresponding 9(1 1 )-dehydro compounds V1 in accordance with methods known in the art, illustratively, with sulfuric acid, with an N-haloamide or N- haloimide and anhydrous sulfur dioxide using the procedure disclosed in U. S. Pat. No. 3,005,834, or with anhydrous sulfur dioxide and an organic base followed by treatment with a halogen (e.g., chlorine, bromine, or iodine) or with a sulfuryl halide (e.g., sulfuryl chloride, bromide or iodide) as disclosed in U. S. Pat. No. 3,441,559.

The compounds of formula VI thus obtained, are then protected by the formation of a 3-enamine or a 3- enol ether. The enamines are prepared by reacting the selected A or A'-"-3-keto steroid V1 with a secondary amine in accordance with methods known in the art, for example, U. S. Pat. Nos. 2,781,342 and 2,886,564; Heyl and Herr, J. Am. Chem. Soc. 75, pages 1913 and S927 (1953) and U. S. Pat. application Ser. No. 801,859, filed Feb. 24, 1969. Representative secondary amines include, for example, dialkylamines such as diethylamine, dipropylamine, diisopropylamine, dibutylamine, dihexylamine, dioctylamine, and didodecylamine; cycloalkylamines such as dicyclohexylamine and the like; cyclic amines such as piperidine, pyrrolidine, tetrahydroquinoline, oxazolidine (tetrahydrooxazole), morpholine, homomorpholine, C-alkylsubstituted pyrrolidine, e.g., 2,4-dimethylpyrrolidine, 3-isopropylpyrrolidine, and 3,3-dimethyl-pyrrolidine, and the like; aralkylalkylamines such as N-methylbenzylamine, N-ethylbenzylamine and the like; substituted dialkylamines such as diethanolamine and the like; and arylalkylamines such as N-methylaniline, N- methyltoluidine, N-methylanisidine, and the like. The secondary cyclic amines are preferred when no A bond is present and when a A -bond is present the dialkylamines are preferred. The A and A -3-keto compounds of formula VI are converted to the corresponding 3-enol ethers of formula VII by known methods, e.g., by reaction with a trialkyl orthoformate such as trimethylorthoformate, triethylorthoformate, tripropylorthoformate and the like, in the presence of a catalyst such as paratoluenesulfonic acid, hydrochloric acid and the like, in accordance with known procedures, e.g., those described in Ber. 71, 1766.

The compounds of formula VII are then subjected to a Grignard reaction at the epoxy group to introduce in one operation, an alkyl group in the 16,8-position and a hydroxyl group in the 17a-position. 1n carrying out the reaction the selected compound of formula VII is reacted with an excess of an alkyl magnesium halide of the formula R MgX, where in R is alkyl as hereinbefore defined and X is bromine, chlorine, or iodine, in accordance with the procedure disclosed in U. S. Pat. No. 3,104,246, to obtain the corresponding 16B-alkyll7a-hydroxy compound of formula VIII.

The compounds of formula Vlll, wherein X is alkoxy as hereinbefore defined, are then subjected to hydrolysis in accordance with methods known in the art to concommitantly remove the 20,2l-acetonide group and the 3-alkoxy group to give the corresponding 13 -3- keto-20,2l-hydroxy compounds of formula X. The hydrolysis is carried out using an aqueous mineral acid, for example hydrochloric, sulfuric, perchloric, hydrobromic and the like, preferably in the presence of a water miscible organic solvent such as ethylene glycol, ethanol, methanol and other lower alkanols, tetrahydrofuran, dimethylformamide, dioxane, and the like, or the hydrolysis can be accomplished using an aqueous organic acid such as formic, acetic, propionic, oxalic, p-toluenesulfonic and the like.

The compounds of formula Xlll, wherein X is the radical as hereinbefore defined, are subjected to alkaline hydrolysis in accordance with known methods, for example using aqueous sodium hydroxide solution to obtain the corresponding compounds of formula IX. The 3-enamine compounds of formula XIII can be isolated from the Grignard reaction medium prior to hydrolysis or they can be hydrolized immediately following the Grignard reaction in a one pot operation. The compounds of formula IX are then isolated from the reaction .medium by known methods an subjected to hydrolysis in the manner disclosed above to remove the 20,21-acetonide group, giving the corresponding compounds of formula X.

The compounds of formula X obtained by either of the above methods are then acylated at the 2l-position in accordance with known methods, to obtain the corresponding compounds of formula XI, for example, with the appropriate acid anhydride or acid halide in the presence of a base such as pyridine. Suitable acylating agents are the acid halides and anhydridesof organic carboxylic acids, particularly hydrocarbon carboxylic acids of one to 18 carbon atoms, such as those hereinbefore listed. Those acids having more than four carbon atoms are more selective to the 2l-position and are therefore preferred. The aromatic and cycloalkane carboxylic acids are especially advantageous.

The intermediates of formula Xl are converted to the known, and pharmacologically active 9a-tluoro-l6B- alkyl-prednisolones, such as Betamethasone, and the corresponding 2l-acylates thereof, in accordance with methods known in the art, for example, as illustratively shown by the following sequenceof formulas:

' HaC-CR XVII wherein R, R and the 1,2-carbon atom linkage have the meanings given hereinabove, and R is hydrogen or acyl as hereinbefore defined. The 2001- and 20B- hydroxy intermediates of formula XI are oxidized at the 20-position to obtain the corresponding 20-ketones of formula XII in accordance with methods known in the art, for example, the selected 20-hydroxy compound X1 is oxidized with a liquid hydrocarbon sulfoxide and sulfur trioxide in the presence of a tertiary amine as disclosed in U. S. Pat. No. 3,444,216; or with a hydrocarbon sulfoxide and an N,N'-di(hydrocarbon substituted) carbodimide in the presence of an acid catalyst as disclosed in U. S. Pat. No. 3,248,380.

The compounds of formula XII and XIII, wherein the l,2-carbon atom linkage is a single bond linkage are dehydrogenated at the l,2-position by a fermentative or chemical dehydrogenation to give the corresponding compounds of formula XIV. Fermentative dehydrogenation comprises the use of microorganisms such as Septomyxa, Corynebacterium, Fusarium, and the like, under fermentation conditions well known in the art (e.g., U. S. Pat. Nos. 2,602,769; 2,902,410 and 2,902,411). Where Septomyxa is used to effect the dehydrogenation it is found to be advantageous to use with the substrate and medium a steroid promoter. The 2l-free alcohols (XIII) are usually employed for the fermentative dehydrogenation process. However, the corresponding 2l-acylates (XII) can be used, in these cases the 2 l -ester group is generally hydrolyzed during the fermentation process giving the corresponding free alcohol (XIV). However, when the 2l-ester substituent is the acyl radical of a high molecular weight acid such as benzoyl, it is preferable to remove the ester group before subjecting the compound to fermentive dehydrogenation because the ester group may inhibit the fermentation reaction. The 2l-ester groups of compound XII can be removed by methods known in the art for example with aqueous sodium hydroxide and the like to give the free alcohols (XIII). Chemical dehydrogenation can be carried out with selenium dioxide according to known procedures, see, for example, Meystre et al., l-Ielv. Chim. Acta, 39, 734 (1956) or with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in a suitable organic solvent such as dioxane or benzene, see, for example, Djerassi, Steroid Reactions, Holden- Day Inc., San Francisco (1963) p. 232. Chemical dehydrogenation can be carried out using either the 21- acylates (XII) or the 2l-free alcohols (XIII). The acylates are generally preferred as starting materials in the selenium dioxide dehydrogenation reaction giving the correspond A"-2l-acylates of formula XIV. The

compounds of formulas XII, XIII and XIV are converted to the 9a-fluoro compounds of formula XVII using the conventional procedure for the introduction of a 9a-fluoro substituent, namely, by reacting the selected compound 9(l1)-compound with N- bromoacetamide and perchloric acid or the like to give the corresponding 9a-bromo compound (XV) followed by treatment with potassium acetate in acetone to form the corresponding 9B,1lB-oxido compound (XVI) and reacting the latter compound with hydrogen fluoride under anhydrous or aqueous conditions to form the desired 9a-fluoro-11B-hydroxy compound (XVII).

The 2l-free alcohols (XVII) are, if desired, reacylated at the 2l-position in accordance with methods hereinbefore described, and 21-acylates (XVII) are, if desired, saponified by known methods to give the corresponding 2 l-free alcohols.

The order of reaction steps for converting the A"- compounds of formula XII to the A -compOundS of XVII can be changed if desired, for example, the ldehydrogenation reaction can be carried out by subjecting a A -compound (XVII) to either chemical or fermentive dehydrogenation as disclosed above, to give the corresponding A -compound of formula XVII.

The following examples describe the manner and process of making and using the invention and set forth the best mode contemplated by the inventors of carrying out the invention but are not to be construed as limiting.

EXAMPLE 1 l l/3,20a,21-trihydroxypregna-4,16dien-3-one(III) A solution of 165.2 g. (0.5 mole) of 113,21- dihydroxypregna-4-cis-17(20)-dien-3-one (I) and 0.6 g. of hematoporphyrin in 500 ml. of dimethylformamide is photo-oxygenated for 130 minutes using a fluorescent lamp while oxygen is bubbled through the solution to give ZOa-hydroperoxy-l1B,2l-dihydroxypregna-4,16-dien-3-one (II). The mixture is then cooled to about 30 C. and 62.04 g. (0.5 mole) of trimethylphosphite is added. The cooling is discontinued and the reaction mixture is allowed to warm to about to C. until an exothermic reaction starts, cooling is then reapplied and the temperature is maintained below 20 C. When thin layer chromatography (hereinafter TLC) indicates that the reaction is complete the mixture is diluted with water and extracted with methylene chloride. The methylene chloride extracts are combined, dried and evaporated to a thick slurry. The slurry is filtered and the solids are dried under vacuum to give 34.0 g. of l1B,20a,21- trihydroxypregna-4,l 6-dien-3-one (III).

A second crop of l1B,20a,2l-trihydroxypregna- 4,16-dien-3-one (17.1 g.) containing a lesser amount of l1B,20B,2l-trihydroxypregna-4,l6-dien-3one (III) is obtained from the mother liquor.

Following the procedure of Example 1, above, but substituting 1 13,21-dihydroxypregna-4trans-17(20)- dien-3-one (I) as starting material in place of the corresponding cis. compound, there is obtained 118,203, 2l-trihydroxypregna-4,l6-dien-3-one (III) as the predominant product. The corresponding 20a-isomer can be recovered from the mother liquors.

In the same manner, following the procedure of Example 1, above, 1lB,21-dihydroxypregn-l,4-cisl7(20)-trien-3-one (I) and 1lB,2l-dihydroxypregna- 1,4trans-17(20)-trien-3-one (I) are converted to 1 1B,20a,2l-trihydroxypregna-l ,4,l6-trien-3-one (III) and l 1B,20B,2l-trihydroxypregna-l ,4,l6-triene-3-one (III), respectively.

EXAMPLE 2 l lfl,20a,21-trihydroxypregna-4,16-dien-3-one, 20a,2l-acetonide (IV) A solution of 23.0 g. (0.066 moles) of llB,20a,2ltrihydroxypregna-4,l6-dien-3-one (III) and 2.0 g. of ptoluenesulfonic acid in 300 ml. of acetone is stirred for about 10 minutes. The solution is neutralized with about 43 ml.-of saturated aqueous sodium bicarbonate solution and then concentrated under vacuum at about 50-60 C. to a thick crystalline slurry. The slurry thus obtained is filtered and the collected solids washed with a small amount of water-acetone (60:40). The solids are then dried under vacuum to' give 21.65 g. (0.056 mole) (84.3 yield) of 1 1B,20a,2l-trihydroxypregna- 4,16-dien-3-one, 20a,21-acetonide (IV), m.p. 17l17 9 C.; [13],, +95 (CI-ICl Following the procedure of Example 2, above, but

' substituting 1 1B,20B,21-trihydroxypregna-4,16-dien-3- one (III) as starting material in place of the corresponding 20a-isomer, there is obtained 116,203,21- trihydroxypregna-4, l 6-dien-3-one, 206,2 1 -acetonide (IV).

In the same manner, following the procedure of Example 2, above, llfl,20a,2l-trihydroxypregna-l,4,l6- trien-3-one (III) and l 1[3,2032l-trihydroxypregna- 1,4,16-trien-3-one (III) are converted to 113,200,21- trihydroxypregna-l ,4,16-trien-3-one 20a,21-acetonide (IV) and l1B,20fl,2l-trihydroxypregna-l,4,16-trien-3- one 206,21-acetonide (IV), respectively.

EXAMPLE 3 1 1B,20a,2 l -trihydroxypregna-4,l6-dien-3-one 2001,21- acetonide (IV) A solution of 81 g. (0.225 mole) of 20a-hydroperoxy-l18,21-dihydroxypregna-4,l6-dien-3-one (II) in dimethylformamide is cooled to about 0 C. and treated with 2l-ml. of trimethyl phosphite while keeping the temperature below 20 C. The reaction mixture is then stirred for about 1 hour at room temperature, treated with 300 ml. of acetone and 12 g. of p-toluenesulfonic acid and stirring is continued for an additional minutes at room temperature. The reaction mixture is then neutralized 'with about 15 ml. of triethylamine and 900 ml. of water is added slowly. The crystalline material thus obtained is cooled to about 20 C. filtered and the collected solids are washed well with cold water and dried to give 51.473 g. (0.1331 mole) (59.1 percent yield) of 11B,20a,2l-trihydroxypregna-4,16- dien-3-one 20a,2l-acetonide (IV), m.p. -174 C.; [11],, +99 (CI-ICI Following the procedure of Example 3, above, but substituting as starting material 2OB-hydroperoxy-1l [3,21-dihydroxypergna-4,l6-dien-3-one (II) in place of the corresponding 20a-isomer, there is obtained 1 lB,20B,21 trihydroxypregna-4,16-dien-3-one 203,21- acetonide (IV).

In the same manner, following the procedure of Example 3, above, 20a-hydroperoxy-l 1B,21-dihydroxypregna-l,4,16-triene-3-one (I1) and 203-hydroperoxy-l 13,2l-dihydroxypregna-l ,4,l6-tiene-3-.one are converted to 1 13,20a,21-trihydroxypregna-1,4,16-trien-3- one 2la,2l-acetonide (IV) and 113,203,2l-trihydroxypregna-l,4,l6-trien-3-one 203,21-acetonide (IV), respectively.

EXAMPLE 4 1 l3,20a,2 l-trihydroxy-l 611,1 7a-oxidopregna-4-en-3- one 20a,21-acetonide (V) A solution of 30.0 g. (0.07762 mole) of 1l3,20a,2ltrihydroxypregna-4,16-dien-3-one 20a,2 1 -acetonide (IV) in about 125 ml. of methylene chloride is cooled to C. with stirring and then a solution of 16.43 g.

(0.0815 mole) of 85.6 percent m-chloroperbenzoic acid in 250 ml. of methylene chloride is added over a period of about 30 min. The reaction mixture is then kept at 05 C. for about 22 hours or until a test of the reaction mixture with starch-iodine paper shows that no peracid is present. The reaction mixture is then filtered to remove crystallized m-chlorobenzoic acid (about 9.0 g.). The filtrate is then washed with 5 percent aqueous sodium bicarbonate solution, water and then dried over anhydrous magnesium sulfate. The filtrate is then evaporated to dryness to give 30.73 g. (0.0763 mole) (98.4 percent yield) of 113,20a,21- trihydroxy-l 6a,17a-oxidopregna-4-en-3-one 2011,21- acetonide (V).

Following the procedure of Example 4, above, but substituting 1 13,203,2 l-trihydroxypregna-4,16-dien-3- one 203,21-acetonide (IV) as starting material in place of the corresponding 20a-isomer, there is obtained 1 l3,203,21-trihydroxy-l601,17a oxidopregna-4-en-3- one 203,21-acetonide (V).

In the same manner, following the procedure of Ex ample 4, above, 113,20a,2l-trihydroxypregna-l,4,l6- trien-3-one 20a,2l-acetonide (IV) and 113,20321- trihydroxypregna-l ,4, 1 6-triene-3-one 203,21 -acetonide are converted to 1 13,20a,2l-trihydroxy-1601,1701- oxidopregna-l,4-dien-3-one 20a,21-acetonide (V) and 1 13,203,21-trihydroxy-l6a,17a-oxidopregna-1,4- dien-3-one 203,21-acetonide (V), respectively.

EXAMPLE 5 2011,21-dihydroxy-l'6a,l7a-oxidopregna-4,9(1 1 )-dien- 3-one 20a,21-acetonide (VI) To a solution of 14.1 g. (0.035 mole) of 113,20a,21- trihydroxy-l611,17a-oxidopregna-4-en-3-one 20,21- acetonide (V) in 30 ml. of dimethylformamide and 30 ml. of pyridine at about 10 C. is added with stirring a solution of 2.9 g. (0.0455 mole) of sulfur dioxide in 5 ml. of pyridine. To the resulting solution is added dropwise a solution of 6.48 g. (0.036 mole; 2.09 ml.) of bromine in ml. of pyridine. Water (165 ml.) is then added slowly. After the addition of the water the reaction mixture is stirred for 45 min. at 05 C., filtered and washed well with water. The solids thus obtained are dried under vacuum at 60 C. to give 13.0 g. (0.0338 mole) (96.6 percent yield) of 2001,21- dihydroxy- 1 6a,17a-oxidopregna-4,9( l l )-dien'-3-one a,2l-acetonide (VI).

Following the procedure of Example 5, above, but substituting 1 13,203,21-trihydroxy-l6a,17a-oxidopregna-4-en-3-one 203,21-acetonide (v) as starting material in place of the corresponding 20a isomer, there is obtained 203,21-dihydroxy-l6a,l7a-oxidopregna-4,9(1 1 )-dien-3-one 203,2l-acetonide (VI).

In the same manner, following the procedure of Example 5,above, ll3,20a,2l-trihydroxy-16a,17a-oxidopregna-l,4-dien-3-one 20a,2l-acetonide (V) and l 13,203,21-trihydroxy-l 601,1 7a-oxidopregna-l ,4- dien-3-one 203,21-acetonide (V) are converted to 20a,2l-dihydroxy-16a,l7a-oxidopregna-1,4,9(1 l trien-3-one 2la,20-acetonide (VI) and 203,21- dihydroxy-l 6a,l7a-oxidopregna-l ,4,9( l l )-trien-3-one 213,20-acetonide (VI), respectively.

EXAMPLE 6 2001,21-dihydroxy-l6a,l7a-oxido-3-(N-pyrrolidyl)- pregna-3,5,9(1 1 )-triene 20a,21-acetonide (VII) Methanol is added to 3.0 g. (0.00780 mole) of 20a,21-dihydroxy-l6a,l7a-oxidopregna-4,9(1 1 )-dien- 3-one 20a,21-acetonide to make a complete solution at reflux. To the refluxing methanol solution under nitrogen is added 0.57 g. (0.0080 mole) of pyrrolidine. The mixture is refluxed for five minutes and then'left to cool to room temperature. The mixture-is then cooled at about 0 C. for about 2 hrs. and filtered. The solids thus obtained are washed well with cold methanol and dried under vacuum to give 3.107 g. (0.00710 mole; 91 percent yield) of 20a,2l-dihydroxy-17a-oxido-3-(N- (VII).

Following the procedure of Example 6, above, but substituting 203,2 l-dihydroxy-l 6a,173-oxidopregna- 4,9(ll)-dien-3-one 203,21-acetonide (VI) as starting material in place of the corresponding 20a-isomer, 203,21-dihydroxy-16a,17a-oxido-3-(N-pyrrolidyl)- pregna-3,5,9(ll )-triene 203,21-acetonide (VII) isobtained. In the same manner, following the procedure of Example 6, above, 2001,21-dihydroxy-16a,l7a-ox- EXAMPLE 7 163-methyl-l7a,20a,21-trihydroxypregna-4,9( l 1)- dien-3-one 2001,21 -acetonide (V11) To a slurry of 5.80 g. (0.01326 mole) of 20a,21- dihydroxy-l 6a,l7a oxido-3-(N-pyrrolidyl)-pregna- 3,5,9(11)-triene-20a,2l-acetonide (VII) in 110 ml. of tetrahydrofuran is added 125 ml. of 3M ethereal methyl magnesium bromide. The resulting slurry is heated with stirring under nitrogen and the solvent is distilled until the pot temperature reaches 90C. The reaction mixture is then refluxed for about 3 hrs., cooled to about C. and 60 ml. of tetrahydrofuran is added to the reaction mixture. This solution is poured into a 0 C. solution of 72 g. of ammonium chloride in 800 ml. of water. The resulting mixture is filtered and the solids are added to a mixture of 18 g. of sodium pyrrolidyl )-pregna-3 ,5 ,9(1 1 )-triene 20a,2 l -acetonide acetate, 18 ml. of water, 120 ml. of methanol and 1 ml. of 50 percent aq. NaOH solution. The resulting mixture is refluxed for about 3 hrs., concentrated to about onethird its original volume and diluted with water. The resulting mixture is extracted with methylene chloride. The methylene chloride extracts are combined, washed with water, dried and evaporated to dryness to give 5.1 g. (0.01275 mole; 96.1 percent yield) of 16B-methyll7a,20a,2 l -trihydroxypregna-4,9(l 1 )-dien-3-one 20a,2l-acetonide (IX). The product thus obtained is dissolved in about 8 ml. of methanol, seeded, allowed to stand overnight at room temperature, cooled at about C. for 2 hrs. and then filtered. The recrystallized product thus obtained is washed with a little cold methanol and dried under vacuum to give 1.6 g. (0.0040 mole; 30.2 percent yield) of 16B-methyl-17 a,20a,21-trihydroxypregna-4,9(l 1)-dien-3-one 20a,2 l -acetonide (IX).

' A second crop of 1.6 g. of 16B-methyl-l7a,20a,2ltrihydroxypregna-4,9( 1 l )-dien-3-one 20a,2l-acetonide (IX) is obtained from themother liquors.

Following the procedure of Example 7, above, but substituting 203,21-dihydroxy-16a,17a-oxido-3-(N- pyrro1idyl)-pregna-3,5,9(1 1)-triene 20B,2l-acetonide (VII) as starting material in place of the corresponding 20a-isomer, 16B-methyl-17a,20B,2l-trihydroxypregna-4,9(11)-dien-3-one 20B,2l-acetonide (IX) is obtained.

In the same manner, following the procedure of Example 7, above, 20a,2l-dihydroxy-l6a,l7a-oxido-3- (N-pyrrolidyl)-pregna-l,3,5,9(11)-tetraene 2001,21- acetonide (VII) and 203,2l-dihydroxy-16a,l7a-oxido- 3-(N-pyrrolidyl)-pregna-1,3,5,9(l1)-tetraene 203,21- acetonide (VII) are converted to 16,8-methyI-17 a,20a,2 1 -trihydroxypregna-1 ,4,9( l 1 )-trien-3-one 20a,2I-acetonide (IX) and l6B-methyI-l7a,20B,2ltrihydroxypregna-l ,4,9( 1 1)-trien-3-one 203,2 1 -acetonide (IX), respectively. 1

EXAMPLE 8 1 6/3-methyl-17a,20a,2 1 -trihydroxypregna-4,9( l I dien-3-one (X) A mixture of 8.5 g. (0.0211 mole) of 16B-methyI-l7 a,20a,2 l -trihydroxypregna-4,9(l 1 )-dien-3-one 20a,2l-acetonide (IX) in about 150 ml. of methanol and 25 ml. of water is treated with 2.5 g. of pyridine hydrochloride and refluxed for about 90 minutes. The reaction mixture is then cooled to room temperature, diluted with about 50 ml. of water, seeded, evaporated under vacuum to a thick crystalline slurry, cooled to about 0 C. and filtered. The solids thus obtained are washed well with water and dried under vacuum at 60 C. to give 16B-methyl-17a,20a,21-trihydroxypregna- 4,9(l1)-dien-3-one (X), m.p. 173174.5 C.; [01],, +68 (CHCI Following the procedure of Example 8, above, but substituting 16B-methyl-l7a,20B,2l-trihydroxypregn- 4,9(ll)-dien-3-one 20B,2l-acetonide (IX) as starting material in place of the corresponding 20a-isomer, 16B-methyl-l7a,20B,2l-trihydroxypregna-4,9(1 1)- dien-3-one (X) is obtained.

In the same manner, following the procedure of Example 8, above, l6B-methyl-l7a,20a,2l-trihydroxypregna-l ,4,9( l l )-trien-3-one 20a,2l-acetonide (IX) and 16B-methyl-l 7a,20B,2 1 -trihydroxypregna-l ,4,9

(1 1)-trien-3-one 20B,2l-acetonide (IX) are converted to 16B-methyll 7a,20a,2 1 -trihydroxypregnal ,4,9 (l 1 )-trien-3-one (X) and l6B-methyl-17a,20B,2ltrihydroxypregna-l,4,9(1 1)-trien-3-one (X), respectively.

EXAMPLE 9 20a,2l-dihydroxy-3-ethoxy-l6a,17a-oxidopregna- 3,5,9(l l )-triene 20a,2I-acetonide (VII) To a stirred slurry of 12.0 g. (0.03121 mole) of 20a,2l-dihydroxy-l6a,l7a-oxidopregna-4,9(1 l )-dien- 3-one 20a,2 l-acetonide (VI) in about 40 ml. of ethanol at room temperature is added 12 ml. of triethylorthoformate and 0.8 g. of pyridine hydrochloride. The reaction mixture is then stirred at room temperature until the reaction is complete, about 2 hours. The reaction mixture is then treated with 0.5 ml. of pyridine and filtered. The solid product thus obtained is washed with a small amount of cold ethanol and dried under vacuum to give 10.8 g. (0.02618 mole, 84 percent yield) of 2001,21-dihydroxy-3-ethoxy- 16a,l7a3,5,9(11)-triene 20a,21-acetonide (VII).

Following the procedure of Example 9, above, but substituting 203,2l-dihydroxy-l6a,l7a-oxidopregna- 4,9(ll)-dien-3-one 20B,21-acetonide (VI) as starting material in place of the 20a-isomer, gives 203,21- dihydroxy-3-ethoxy-l6a,17a-oxidopregna-3,5,9(1 1)- triene 20B,21acetonide (VII).

In the same manner, following the procedure of Example 9, above, 2001,21 -dihydroxy-l6 a,1 7a-oxidopregnal ,4,9(1 1)-triene-3-one 20a,2 l -acetonide (XI) and 205,2 l-dihydroxy- 1 6a, 1 7a-oxidopregna- 1,4,9(1 l )-trien-3-one 20/3,21-acetonide (VI) to give 20a,21-dihydroxy-3-ethoxy-16a,17a-oxidopregna- 1,3,5,9(1 l )-tetraene 20a,2l-acetonide (VII) 203,2l-dihydroxy-3-ethoxy-16a,17a-oxidopregna- 1,3,5,9,(1l-tetraene 2013,21-acetonide (VII), respectively. EXAMPLE 1O 1 6B-methyl-17a,20a,2l-trihydroxy-3-ethoxypregna- 3,5,9(1 1)-triene 20a,21-acetonide (VIII) A solution of 10.0 g. (0.02424 mole) of 2001,21- dihydroxy-3-ethoxy-l6a, l 7a-oxidopregna-3,5,9(l 1)- triene 20a,2l-acetonide in 165 ml. of tetrahydrofuran is added at room temperature with stirring to 162 ml. of 3M methyl magnesium bromide in ethyl ether. The resulting solution is heated with stirring under nitrogen and the solvent is distilled until the pot temperature reaches about 88 C. The reaction mixture is then refluxed for about min. or until the reaction is complete. The reaction mixture is then cooled to about 60 C. and 100 ml. of tetrahydrofuran is added with stirring. The resulting solution is poured slowly into a 0 C. solution of 97 g. of ammonium chloride in 1,500 ml. of water. The slurry thus obtained is stirred for 40 min, and then filtered. The solids thus obtained are washed with water and then dried under vacuum at 60 C. to give 10.41 g. of product, which is titurated with 15 ml. of ethanol and 10 ml. of methanol, cooled to 0 C. and filtered. The solids thus obtained are washed with a little cold methanol and dried under vacuum at 60 C. to give 9.0 g. (0.0210 mole; 86.6 percent yield) of methyl- 1 7a,20a,2 l -trihydroxy-3-ethoxypregna- 3,5,9(11)-triene 20a,21-acetonide (VII), l76.5-185.5 C.; 11 1 58 (CHCI pyridine).

and

16B-methyl-17a,20a,21-trihydroxypregna-4,9(11)- Following the procedure of Example 10, above, but substituting 203,2l-dihydroxy3-ethoxy-l6a,l7a-oxidopregna-3,4,9( l l )-triene-20B,2 1 -acetonide (VII) as starting material in place of the corresponding 20aisomer, l6B-methyl-l7a,20B,2l-trihydroxy-3-ethoxypregna-3,5,9(1 1)-triene 2OB,21-acetonide (VIII) is obtained.

In the same manner, following the procedure of Example 10, above, 20a,21-dihydroxy-3-ethoxy-l601,170:- oxidopregna-l ,3,5,9( 1 l )-tetraene 20a,2l-acetonide (VII) and 203,21-dihydroxy-3-ethoxy-l6a,I7a-oxidopregna-l ,3,5 ,9( 1 l )-tetraene 203,2 1 -acetonide (VII) are converted to 16B-methyl-17a,20a,2ltrihydroxy-3-ethoxy-pregna-1,3,5,9( l 1)-tetraene 20a,21-acetonide (VIII) and l6B-methyl-l7a,20fl,21- trihydroxypregna-l,3,5,9(1 1 )-tetraene 20B,21-acetonide (VIII), respectively.

EXAMPLE 1 I diene-3-one (X) A mixture of 8.5 g. (0.0200 mole) of l6B-methyl-I7 a,20,21-trihydroxy-3-ethoxy-pregna-3,5,9(1 1)-triene 20a,2l-acetonide (VIII), 130 ml.,of methanol, 30 ml. of chloroform, 20 ml. of water and 2.5 g. of ptoluenesulfonic acid is refluxed for about 90 minutes, cooled to room temperature, diluted with 25 ml. of water, seeded and evaporated to a thick crystalline slurry under vacuum in a 50-60 C. water bath. The mixture is then cooled to C. and filtered. The solids thus obtained are washed well with water and dried under vacuum at 60 C. to give 6.71 g. (0.01861 mole;

EXAMPLE l2 l6B-methyl-17a,20a,2l-trihydroxypregna-4,9( l I diene-3-one 21-benzoate (XI) A solution of 6.31 g. (0.0175 mole) of 16/3-methy1- 17a,20,21-trihydroxypregna-4,9( 1 1)-dien-3-one (X) in 100 ml. of dioxane and 12 ml. of pyridine is stirred at room temperature under nitrogen. To this solution is added 2.46 g. (0.0175 mole) of benzoyl chloride. After stirring the solution for about minutes, an additional 2.46 g. of benzoyl chloride is added and stirring is continued until the reaction is complete, about min. Water 100 ml.) is then added dropwise to the reaction mixture. The resulting slurry is cooled to about 0 C., filtered and the solids are washed well with water. The

solids thus obtained are titurated with 30 ml. of diethyl ether, filtered and dried under vacuum to give 7.365 g. (0.01585 mole) (90.5 percent yield) of 16/3-methyl-l7 a,20a,2 l -trihydroxypregna-4,9,( l l )-dien-3-one 21- benzoate (XI), m.p. l72.5181 C., [01],, +58 (CHCI Following the procedure of Example 12, above, but substituting IGB-methyll 7a,20B,2 I -trihydroxypregna- 4,9(1 l )-dien-3-one (X) as starting material in place of the corresponding ZOa-isomer, 16B-r'nethyl-l7 a,20fi,2 l -trihydroxypregna-4,9( 1 l )-dien-3-one 21 benzoate (XI) is obtained.

In the same manner, following the procedure of Example 12, above, l6,6-methyl-l7a,20a,2l-trihydroxypregna-l,4,9(l1)-trien-3-one (X) and l6B-methyl-l7 (1,203,21-trihydroxypregna-l,4,9(1l)-trien-3-one (X) are converted to 16B-methyl-17u,20a,2I-trihydroxypregna-1,4,9(1 l )-trien-3-one 21-benzoate (XI) and I6B-methyl-l7a,20B,21-trihydroxypregna-l,4,9(l 1)- trien-3-one 2l-benzoate (XI), respectively.

EXAMPLE l3 l6B-methyl-l7a,2l-dihydroxypregna-4,9( l l )-diene- 3,20-dione 2-l-benzoate (XII) A solution of 13 g. of pyridine sulfur trioxide complex in 50 ml. of dimethylsulfoxide is added dropwise over a period of about 6 min. to a vigorously stirred mixture of 7.0 g. (0.01507 mole) of 16B-methyl-l7 a,20a,2l-trihydroxy-4,9(1 l )-pregnadien-3-one 2lbenzoate (XI) in 37 ml. of dimethylsulfoxide and 34 ml. of triethylamine, while keeping the temperature at about 20 C. The resulting mixture is then stirred at room temperature for about 1 hr. The pH of the mixture is adjusted to 4.5 by the addition of 18 percent aq. HCI. The mixture is then diluted with water and filtered. The solids thus obtained are washed with water and dried under vacuum to give 6.95 g. of partially oxidized product. The product (6.95 g.) thus obtained is oxidized again using the same procedure as above to give 6.9 g. of material, which is triturated with 30 ml. of methanol to give 5.70 g. (0.01232 mole) (81.7 percent yield) of oxidized product. The product thus obtained is crystallized from methanol to give 4.7 g. of I613- methyl-1701,21-dihydroxypregna-4,9( l l )-dien-3,20-

dione 2l-benzoate (XII), m.p. l98.5203.5 C.; [01],,

+167 (CHCl Following the procedure of Example 13, above, but substituting l6B-methyl-l 7a,20fi,2l-trihydroxypregna- 4,9(1l)-diene-3-one 2l-benzoate (XI) as starting material in place of the corresponding 20a-isomer, 16B-methyl-l7a,21-dihydroxypregna-4,9(1 1)-dien- 3,20-dione 2l-benzoate (XII) is obtained.

In the same manner, following the procedure of Example 13, above, 16B-methyl-l7a,20a,2l-trihydroxypregna-1,4,9(ll)-triene-3-one 2l-benzoate (XI) and I6B-methyl-17a,20B,21-trihydroxypregna-l ,4,9( l 1)- triene-3-one 2l-benzoate (XI) are converted to 163- methyl-17a,2l -dihydroxypregna-1,4,9( 1 l )-trien-3,20- dione 2l-benzoate (XII) and l6B-methyl-17a,2ldihydroxypregna-l ,4,9(1 I )-trien-3,20-dione 2 1 benzoate (XII), respectively.

EXAMPLE 14 l6B-methyl-l 701,2 1 -dihydroxypregna-l ,4,9( l l )-triene- 3,20-dione 21-benzoate (XIV) A mixture of 5.0 g. of 16B-methyl-l7a,21-dihydroxypregna-4,9(1l)-diene-3,20-dione 21-benzoate (XII), 3.0 g. of selenium dioxide, 250 ml. of tert.-butylalcohol and 1 ml. of pyridine is refluxed for 24 hours. An additional 0.5 g. of selenium dioxide is then added to the reaction mixture and refluxing is continued for about 3 more hours. The reaction mixture is then filtered with the aid of celite and the filter pad is washed with ethyl acetate. The filtrate thus obtained is concentrated to dryness under vacuum and the residue is chromatographed over silica gel to give 3.0 g. of 16B-methyl-l7 a,21-dihydroxypregna-I,4,9(11)-triene-3,20-dione 21- benzoate (XIV).

In the same manner, following the procedure of Example 14, the other 16B-alkyl-17a,21-dihydroxypregna-4,9( 1 1)-diene-3,20-diones 2l-acylates (XII) and 21-free alcohols of formula XIII are likewise converted to the corresponding l6B-alkyl-17a,2ldihydroxypregna-1,4,9(11)-triene-3,20-dione 21 acylates and 21-free alcohols, respectively of formula (XIV).

EXAMPLE l5 9a-bromo-l 6B-methyl-l 113,17a,2l-trihydroxypregna- 1,4-diene-3,20-dione 21-benzoate (XV) A solution of 10.4 g. of 16B-methyl-17a,21- dihydroxypregna-l ,4,9( 1 l )-triene-3,20-dione 21- benzoate (XIV) in 90 ml. of tetrahydrofuran is cooled to about 15 C. and treated with 48 ml. of 0.47N aqueous perchloric acid followed by 4.1 g. of N-bromoacetmaide. After stirring 4 hours in the dark at 2530 C. enough saturated aqueous sodium sulfite solution is added to the reaction mixture to discharge the excess hypybromous acid. The mixture is poured slowly into ice water. The resulting precipitate is collected by filtration, washed neutral with water and dried to give 11.6 g. of 9a-bromo-16B-methyl-l lB,l7a,21- trihydroxypregna-l ,4-diene-3,20-dione 21-benzoate (XV).

In the same manner, following the procedure of Example 15, other compounds of formula XIV and the compounds of formulas XII and XIII can likewise be.

EXAMPLE 16 1701,2l-dihydroxy-l6B-methyl-9B,1 lfl-oxidopregnal,4-dien-3,20-dione (XVI) A stirred solution of 23.9 g. of 9a-bromo-l6B methyl-1 1B,17a,2I-trihydroxypregnal ,4-diene-3,20- dione 2l-benzoate (XV) in 1,060 ml. of a methanolchloroform mixture (3:2) is treated in a nitrogen atmosphere at -5 C. with 88 ml. of 1N sodium hydroxide solution added dropwise over 50 minutes. Stirring is continued for about 3 hours and the mixture is neutralized by the addition of acetic acid. The solution is concentrated under reduced pressure to a thick crystalline slurry which is poured into 1,060 ml. of ice water. The resulting precipitate is filtered, washed neutral with water and dried under vacuum to give 14.3 g. of 1701,21-dihydroxy-l6B-methyl-9B,1 lfl-oxidopregna- 1,4-diene-3,20-dione (XVI) m.p. 23 l239 C.

In the same manner, following the procedure of Example 16, the other Qa-bromo compounds of formula XV are likewise converted to the corresponding 93,11Boxid0 compounds offormula XVI.

EXAMPLE 17 of potassium carbonate in 210 ml. of water. The result-' ing precipitate is filtered, washed to neutrality with water and dried to give 22.2 g. of crude product. Crystallization from ethyl acetate gives 17.6 g. of 9afluoro-l 113,1 7a,21-trihydroxy-l 6B-methylpregna-l ,4- diene-3,20-dione m.p. 241-243 C. (XVII).

In the same manner, following the procedure of Example 17, the other 9B,11B-oxido compounds of formula XVI are likewise converted to the corresponding 9a-fluoro compounds of formula XVII.

EXAMPLE 18 20a,2l-dihydroxy, l6a,l7a-oxido-3- diethylaminopregna-l ,3,5,9( 1 l )-tetraene 2001,21- acetonide (VII) To a solution of 6 ml. diethylamine in ml. of dry benzene at 15 is slowly added 0.5 ml. of titanium tetrachloride in 10 ml. of benzene. After stirring 30 minutes, this titanium chloride-amine complex is then added over 30 minutes to a solution of 1.8 g. of 2004,21- dihydroxy-16a,l7a oxido-1,4,9(1 1)-trien-3-one a,21-acetonide (VI) in 10 ml. of dry methylene chloride at room temperature. After the addition, this heterogeneous mixture is stirred at 5 for 3 hours after which 0.2 ml. of water in 1 ml. diethylamine is added with vigorous stirring. The resulting precipitate is filtered over sodium sulfate, washed with benzene and the filtrate is evaporated to dryness under vacuum. The residue thus obtained is triturated with cold methanol to give 20a,21-dihydr0xy-1 601,1 7a-oxido-3- diethylaminopregna-l ,3,5,9( 1 l)-tetraene 2011,21- acetonide (VII).

Following the precedure of EXample 18, above, but substituting 208,2l-dihydroxy-l6a,17a-oxido-l ,4,9 (l l )-trien-3-one 20B,21-acetonide (V1) as starting material in place of the corresponding 20a-isomer, 20,8,2l-dihydroxy-16a,l7a-oxido-3- diethylaminopregna-l ,3,5,9( 1 1 )-tetraene acetonide (VII) is obtained.

The 20a,2I-dihydroxy-l6a,17a-oxido-3- diethylaminopregna-l,3,5,9(1 1)-tetraene 2004,21- acetonide (VII) and 20B,2l-dihydroxy-16a,17a-oxido- 3-diethylaminopregna-l,3,5,9(11)-tetraene acetonide (VII) are converted to 16/3-methyl-l7 a,20a,2l-trihydroxypregna-l,4,9(11)-trien-3-one 20a,2l-acetonide (VIII) and 16B-methyl-l7a,20B,21- trihydroxypregnal ,4,9(1 1)-trien-3-one 2OB,21-acetonide, respectively, in accordance with the procedure of Example 7, above.

We claim:

1. A compound of the formula:

l --on f TC:

wherein R is hydrogen or the a cyl radical o f a hydrocarbon carboxylic acid of one to 18 carbon atoms, inclusive, and the l,2-carbn atom linkage is a single bond linkage or a double bond linkage.

2. l6B-methyll 7a,20a,2 l -trihydroxypregna-4,9 (ll)-dienl3-one, the compound of claim 1, wherein R is hydrogen and the 1,2-carbon atom linkage is a single bond linkage.

3. l6B-methyl-17a,20a,2l-trihydroxypregna-4,9

(1l)-dien-3-one Zl-benzoate, the compound of claim 1, wherein R is benzoyl and the 1,2-carbon atom linkage is a single bond linkage.

4. A pqqqiQf ttxqfsz m (ll)-dien-3-one 20a,2jl-acetonide,, the. compound. of claim 4, wherein R and, R are each methyl and.v the l,2-carbon atomlinkage is a singlebondlinkage.

6. A compougd of thgformula:

wherein R and R taken separately are each selected from the group-consistingof hydrogen, analkylradical of l to 8 carbonatoms, inclusive,an aralkyl radical of-'7 to 12 carbon atoms, inclusive, and an aryl'radical. of 6 to 12 carbon atoms, ,inclusiveyR and R2 takentogether with the attached carbon atomrepresent a cycloalkyl radical of 3 to 6 carbonatoms, inclusive;.X, isan alkoxy radical of l to 12 carbon'atoms, inclusive; and the l,2-carbon atom linkage is a single bond linkage or a double bond linkage.

7. l6B-methyl-l7a,20a,2l-trihydroxy-3-ethoxypregna-3,5,9( l l )-triene 2001,2l-acetonid, the compound of claim 6, wherein R and R are each methyl, X, is ethoxy and the l,2-carbon atom linkageis a single bond linkage.

8. A compound of the formula:

wherein R and R taken separately are selected from the group consisting of hydrogen, an alkyl radical of one to eight carbon atoms, inclusive, an aralkyl radical of seven to 13 carbon atoms,-inclusive, and an aryl radical of six to 12 carbon atoms, inclusive; R and R taken together with the attached carbon atom represent a cycloalkyl radical of three to six carbon atoms, inclusive; X is selected from the group consisting of an alkoxy radical of one to 12 carbon atoms, inclusive, and theradical,

in which R, and R taken separately are each alkyl as hereinbefore defined and R and R taken togeth'erwith constitute-{saturated hete gcyclic am'ino' radical,

of from. five to nine ring atoms, inclusive; and the l,2.-carbon atom linkage is a single bond linkage or a double bond linkage.

9. 2001,21-dihydroxy-3-ethoxy-l 604,1 lot-oxidopregna--3,5,9(l l )-triene 20a,21-acetonidej, the

compound of claim 8 wherein R and R aree'ach methyl, X is ethoxy and the l,2-carbon atom linkage is a single bond linkage. v

10; 20a,2 l -dihydroxy-l 601, l 7a-oxido-3-(N-pyrrolidyl')-pregna-3,5,9( l l )-triene 20a,2 l -acet'onid'e, the compound of claim 8' wherein R and R are each methyl, X is N-pyrrolidyl and the l,2-carbon atom linkage is a single bond linkage.

l l. A compound of the formula:

wherein R, and R taken separately are each selected from the group consistingofhydrogen, an alkyl radicalof one to eight carbon atoms, inclusive, an aralkyl radical of seven to 13 carbon atoms, inclusive, and an aryl radical of six to 12 carbon atoms, inclusive; R and R radical of six to 12 carbon atoms, inclusive; R and R taken together represent a cycloalkyl radical of six to taken together represent a cycloalkyl radical of six to 12 carbon atoms inclusive; and the 1,2-carbon atom 12 carbon atoms, inclusive; and the l,2-carbon atom linkage is a single bond linkage or a double bond linklinkage is a single bond linkage or a double bond link- 5 age, with a peracid to :ota 1i n the gofresponding age. 1ea,"'17a oxiuo compound.

12. 1 1B,20a,21-trihydroXy-l6a,l7a-oxidopregna-4- 2. dehydrating the l6a,17ct-0Xid0 compound so en-3-one 20a,2l-acetonide, the compound of claim 11, obtained with a dehydrating agent to obtain the wherein R and R are each methyl and the l,2-carbon corresponding 16 ,17 id -9(11)-d h d atom linkage is a single bond linkage. 10 compound;

A compound of the formula: 3. reacting the 16a,17a-oxido-9( l 1 )-dehydro com- Hil -'6 it; pound so obtained with a secondary amine of the' formula HC- O R, i V

Ho HN 1 2 20 in which R, and R taken separately are each alkyl 0: and R and R taken together with wherein R and R taken separately are each selected from the group consisting of hydrogen, an alkyl radical H N of one to eight carbon atoms, inclusive, an aralkyl radical of seven to 13 carbon atoms, inclusive, and an aryl radical of six to 12 carbon atoms, inclusive; R and R th 3 th taken together represent a cycloalkyl radical of six to e corresPon mg enanime ereo 12 carbon atoms, inclusive; and the l,2carbon atom reacting the 3'.enamme so obtained with linkage is a single bond linkage or a double bond linkmagnesmm hahde of the formula RSMSX m which constitute a saturated heterocyclic amine, to obtain age. R is an alkyl radical as defined above and X is 14. llB,20a,2l-trihydroxypregna-4,l6-dien-3one bmmme the 20a,21-acetonide, the compound of claim 13, wherein reswndfng l6fi'alkyl'3'enamme; R and R are each methyl and the 1,3-carbon atom sublecufig the r alkalme linkage is a Single bond linkage 35 hygrolysis to regenerate the A -3-keto ring system an jifljgf of the production of a compound of 6. subjecting the A-3-keto 16B-alkyl-20,21-aceto- H nide compound so obtained to acid hydrolysis with HMNOH an aqueous mineral acid to remove the 20, 21-

40 acetonide group. I f R5 16. The process of claim 15 for the production of I 16B methyl- 17a,20a,2l-trihydroxypregna-4,9( l l dien-3-one, wherein the starting material is 2001,21-

dihydroxypregna-4, 16-dien-3-one 20a,2 l-acetonide and the alkyl magnesium halide is methyl magnesium 0: bromide.

wherein R is an alkyl radical of one to eight carbon The process for the producuon ofa compound of the formula:

atoms, inclusive, and the l,2carbon atom linkage is a single bond linkage or a double bond linkage, which comprises: a a. l epoxidizing a 20,2 1 -acetonide of the formula:

I IICO R1 C H I NWO/ \R, HO-

on wherein R is an alkyl radical of one to eight carbon wherein R, and R taken separately are each selected atoms, inclusive, and the 1,2carbon atom linkage is a from the group consisting of hydrogen, an alkyl radical single bond linkage or a double bond linkage, which of one to eight carbon atoms, inclusive, an aralkyl radicomprises:

cal of seven to 13 carbon atoms, inclusive, and an aryl l. epoxidizing a 20,2l-acetonide of the formula:

wherein R, and R taken separately are each selected from the group consisting of hydrogen, an alkyl radical of one to eight carbon atoms, inclusive, an aralkyl radical of seven to 13 carbon atoms, inclusive, and an aryl radical of six to 12 carbon atoms, inclusive; R and R taken together represent a cycloalkyl radical of six to 12 carbon atoms, inclusive; and the 1,2-carbon atom linkage is a single bond linkage or a double bond link 16a, l 7lx oxido compound 2. dehydrating the 16a,17a-oxido compound so obto acid hydrolysis with an aqueous mineral acid toconcommitantly regenerate the A-3-keto ring system and remove the 20,2l-acetonide group. 18. The process of claim 17 for the production of l 6B-methyll 7a,20a,2 l-trihydroxypregna-4,9( l 1 dien-3-one, wherein the starting material is 2001,21- dihydroxypregna-4,16-dien-3-one 20a,2 l-acetonide and the alkyl magnesium halide is methyl magnesium bromide. 

2. 16 Beta -methyl-17 Alpha ,20 Alpha ,21-trihydroxypregna-4, 9(11)-dien-3-one, the compound of claim 1, wherein R is hydrogen and the 1,2-carbon atom linkage is a single bond linkage.
 2. dehydrating the 16 Alpha ,17 Alpha -oxido compound so obtained with a dehydrating agent to obtain the corresponding 16 Alpha ,17 Alpha -oxido-9(11)-dehydro compound;
 2. dehydrating the 16 Alpha ,17 Alpha -oxido compound so obtained with a dehydrating agent to obtain the corresponding 16 Alpha ,17 Alpha -oxido-9(11)-dehydro compound;
 3. reacting the 16 Alpha ,17 Alpha -oxido-9(11)-dehydro compound so obtained with a trialkyl orthoformate to obtain the corresponding 3-enol ether;
 3. reacting the 16 Alpha ,17 Alpha -oxido-9(11)-dehydro compound so obtained with a secondary amine of the formula
 3. 16 Beta -methyl-17 Alpha ,20 Alpha ,21-trihydroxypregna-4, 9(11)-dien-3-one 21-benzoate, the compound of claim 1, wherein R is benzoyl and the 1,2-carbon atom linkage is a single bond linkage.
 4. A compound of the formula:
 4. reacting the 3-enamine so obtained with an alkyl magnesium halide of the formula, R5MgX in which R5 is an alkyl radical as defined above and X is chlorine, bromine or iodine, to obtain the corresponding 16 Beta -alkyl-3-enamine;
 4. reacting 3-enol ether so obtained with an alkyl magnesium halide of the formula, R5MgX in which R5 is an alkyl radical as defined above and X is chlorine, bromine or iodine, to obtain the corresponding 16 Beta -alkyl-3-enol ether; and
 5. subjecting the 16 Beta -alkyl-3-enol ether so obtained to acid hydrolysis with an aqueous mineral acid to concommitantly regenerate the Delta 4-3-keto ring system and remove the 20, 21-acetonide group.
 5. subjecting the 16 Beta -alkyl-3-enamine to alkaline hydrolysis to regenerate the Delta 4-3-keto ring system and;
 5. 16 Beta -methyl-17 Alpha ,20 Alpha ,21-trihydroxypregna-4, 9(11)-dien-3-one 20 Alpha ,21-acetonide, the compound of claim 4, wherein R1 and R2 are each methyl and the 1,2-carbon atom linkage is a single bond linkage.
 6. A compound of the formula:
 6. subjecting the Delta 4-3-keto 16 Beta -alkyl-20,21-acetonide compound so obtained to acid hydrolysis with an aqueous mineral acid to remove the 20, 21-acetonide group.
 7. 16 Beta -methyl-17 Alpha ,20 Alpha ,21-trihydroxy-3-ethoxypregna-3,5,9(11)-triene 20 Alpha ,21-acetonide, the compound of claim 6, wherein R1 and R2 are each methyl, X1 is ethoxy and the 1,2-carbon atom linkage is a single bond linkage.
 8. A compound of the formula:
 9. 20 Alpha ,21-dihydroxy-3-ethoxy-16 Alpha ,17 Alpha -oxidopregna-3,5,9(11)-triene 20 Alpha ,21-acetonide, the compound of claim 8, wherein R1 and R2 are each methyl, X is ethoxy and the 1,2-carbon atom linkage is a single bond linkage.
 10. 20 Alpha ,21-dihydroxy-16 Alpha ,17 Alpha -oxido-3-(N-pyrrolidyl)-pregna-3,5,9(11)-triene 20 Alpha ,21-acetonide, the compound of claim 8 wherein R1 and R2 are each methyl, X is N-pyrrolidyl and the 1,2-carbon atom linkage is a single bond linkage.
 11. A compound of the formula:
 12. 11 Beta ,20 Alpha ,21-trihydroxy-16 Alpha ,17 Alpha -oxidopregna-4-en-3-one 20 Alpha ,21-acetonide, the compound of claim 11, wherein R1 and R2 are each methyl and the 1,2-carbon atom linkage is a single bond linkage.
 13. A compound of the formula:
 14. 11 Beta ,20 Alpha ,21-trihydroxypregna-4,16-dien-3-one 20 Alpha ,21-acetonide, the compound of claim 13, wherein R1 and R2 are each methyl and the 1,3-carbon atom linkage is a single bond linkage.
 15. The process of the production of a compound of the formula:
 16. The process of claim 15 for the production of 16 Beta -methyl-17 Alpha ,20 Alpha ,21-trihydroxypregna-4,9(11)-dien-3-one, wherein the starting material is 20 Alpha ,21-dihydroxypregna-4,16-dien-3-one 20 Alpha ,21-acetonide and the alkyl magnesium halide is methyl magnesium bromide.
 17. The process for the production of a compound of the formula:
 18. The process of claim 17 for the production of 16 Beta -methyl-17 Alpha ,20 Alpha ,21-trihydroxypregna-4,9(11)-dien-3-one, wherein the starting material is 20 Alpha ,21-dihydroxypregna-4,16-dien-3-one 20 Alpha ,21-acetonide and the alkyl magneSium halide is methyl magnesium bromide. 